TAK1 activates NF-kB by phosphorylation and activation of IKK complex (Homo sapiens)

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Bibliography

1. Bonizzi G, Karin M.; ''The two NF-kappaB activation pathways and their role in innate and adaptive immunity.''; PubMed Europe PMC Scholia
2. Thiefes A, Wolter S, Mushinski JF, Hoffmann E, Dittrich-Breiholz O, Graue N, Dörrie A, Schneider H, Wirth D, Luckow B, Resch K, Kracht M.; ''Simultaneous blockade of NFkappaB, JNK, and p38 MAPK by a kinase-inactive mutant of the protein kinase TAK1 sensitizes cells to apoptosis and affects a distinct spectrum of tumor necrosis factor [corrected] target genes.''; PubMed Europe PMC Scholia
3. Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ.; ''TAK1 is a ubiquitin-dependent kinase of MKK and IKK.''; PubMed Europe PMC Scholia
4. Arch RH, Gedrich RW, Thompson CB.; ''Tumor necrosis factor receptor-associated factors (TRAFs)--a family of adapter proteins that regulates life and death.''; PubMed Europe PMC Scholia
5. Häcker H, Karin M.; ''Regulation and function of IKK and IKK-related kinases.''; PubMed Europe PMC Scholia
6. Krappmann D, Hatada EN, Tegethoff S, Li J, Klippel A, Giese K, Baeuerle PA, Scheidereit C.; ''The I kappa B kinase (IKK) complex is tripartite and contains IKK gamma but not IKAP as a regular component.''; PubMed Europe PMC Scholia
7. Lamothe B, Besse A, Campos AD, Webster WK, Wu H, Darnay BG.; ''Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation.''; PubMed Europe PMC Scholia
8. Cui J, Zhu L, Xia X, Wang HY, Legras X, Hong J, Ji J, Shen P, Zheng S, Chen ZJ, Wang RF.; ''NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways.''; PubMed Europe PMC Scholia
9. Chen ZJ.; ''Ubiquitin signalling in the NF-kappaB pathway.''; PubMed Europe PMC Scholia
10. Yazdi S, Naumann M, Stein M.; ''Double phosphorylation-induced structural changes in the signal-receiving domain of IκBα in complex with NF-κB.''; PubMed Europe PMC Scholia
11. Rothwarf DM, Zandi E, Natoli G, Karin M.; ''IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex.''; PubMed Europe PMC Scholia
12. Jacobs MD, Harrison SC.; ''Structure of an IkappaBalpha/NF-kappaB complex.''; PubMed Europe PMC Scholia
13. Gil J, Alcamí J, Esteban M.; ''Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complex.''; PubMed Europe PMC Scholia
14. Adhikari A, Xu M, Chen ZJ.; ''Ubiquitin-mediated activation of TAK1 and IKK.''; PubMed Europe PMC Scholia
15. Rushe M, Silvian L, Bixler S, Chen LL, Cheung A, Bowes S, Cuervo H, Berkowitz S, Zheng T, Guckian K, Pellegrini M, Lugovskoy A.; ''Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site.''; PubMed Europe PMC Scholia

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External references

DataNodes

Name	Type	Database reference	Comment
ADP	Metabolite	CHEBI:16761 (ChEBI)
AGER [plasma membrane]	Protein	Q15109 (Uniprot-TrEMBL)
AGER ligands:AGER	Complex	REACT_24620 (Reactome)
APP(672-711) [extracellular region]	Protein	P05067 (Uniprot-TrEMBL)
APP(672-713) [extracellular region]	Protein	P05067 (Uniprot-TrEMBL)
ATP	Metabolite	CHEBI:15422 (ChEBI)
Activated IKK Complex	Complex	REACT_7826 (Reactome)
Activated TAK complexes	Complex	REACT_23279 (Reactome)
CHUK [cytosol]	Protein	O15111 (Uniprot-TrEMBL)
HMGB1 [extracellular region]	Protein	P09429 (Uniprot-TrEMBL)
IKBKB [cytosol]	Protein	O14920 (Uniprot-TrEMBL)
IKBKG [cytosol]	Protein	Q9Y6K9 (Uniprot-TrEMBL)
IKKA:IKKB:NEMO	Complex	REACT_7693 (Reactome)
IkBs:NFkB	Complex	REACT_7272 (Reactome)
K63polyUb TRAF6 [cytosol]	Protein	Q9Y4K3 (Uniprot-TrEMBL)
MAP3K7 [cytosol]	Protein	O43318 (Uniprot-TrEMBL)
MDP [cytosol]	Metabolite	CHEBI:59414 (ChEBI)
N-epsilon-(1-(1-carboxy)ethyl)lysine [extracellular region]	Metabolite	CHEBI:60125 (ChEBI)
NECML [extracellular region]	Metabolite	CHEBI:53014 (ChEBI)
NFKB1(1-433) [cytosol]	Protein	P19838 (Uniprot-TrEMBL)
NFKB1(1-433) [nucleoplasm]	Protein	P19838 (Uniprot-TrEMBL)
NFKB2(1-454) [cytosol]	Protein	Q00653 (Uniprot-TrEMBL)
NFKB2(1-454) [nucleoplasm]	Protein	Q00653 (Uniprot-TrEMBL)
NFKBIA [cytosol]	Protein	P25963 (Uniprot-TrEMBL)
NFKBIB [cytosol]	Protein	Q15653 (Uniprot-TrEMBL)
NFkB Complex	Complex	REACT_7108 (Reactome)
NFkB Complex	Complex	REACT_7143 (Reactome)
NOD1 [cytosol]	Protein	Q9Y239 (Uniprot-TrEMBL)
NOD2 [cytosol]	Protein	Q9HC29 (Uniprot-TrEMBL)
Peptide [extracellular region]	Metabolite	CHEBI:16670 (ChEBI)
Phospho-NF-kappaB Inhibitor	Protein	REACT_7645 (Reactome)
RELA [cytosol]	Protein	Q04206 (Uniprot-TrEMBL)
RELA [nucleoplasm]	Protein	Q04206 (Uniprot-TrEMBL)
S100A12 [extracellular region]	Protein	P80511 (Uniprot-TrEMBL)
S100B [extracellular region]	Protein	P04271 (Uniprot-TrEMBL)
SAA1(19-122) [extracellular region]	Protein	P0DJI8 (Uniprot-TrEMBL)
TAB1 [cytosol]	Protein	Q15750 (Uniprot-TrEMBL)
TAB2 [cytosol]	Protein	Q9NYJ8 (Uniprot-TrEMBL)
TAB2 [plasma membrane]	Protein	Q9NYJ8 (Uniprot-TrEMBL)
TAB3(1-712) [cytosol]	Protein	Q8N5C8 (Uniprot-TrEMBL)
TAB3(1-712) [plasma membrane]	Protein	Q8N5C8 (Uniprot-TrEMBL)
Ub-209-RIPK2 [cytosol]	Protein	O43353 (Uniprot-TrEMBL)
iE-DAP [cytosol]	Metabolite	CHEBI:59271 (ChEBI)
p-2S,S376,T,T209,T387-IRAK1 [cytosol]	Protein	P51617 (Uniprot-TrEMBL)	This is the hyperphosphorylated, active form of IRAK1. The unknown coordinate phosphorylation events are to symbolize the multiple phosphorylations that likely take place in the ProST domain (aa10-211).
p-IRAK2 [cytosol]	Protein	O43187 (Uniprot-TrEMBL)
p-S176,S180-CHUK [cytosol]	Protein	O15111 (Uniprot-TrEMBL)
p-S177,S181-IKBKB [cytosol]	Protein	O14920 (Uniprot-TrEMBL)
p-T184,T187-MAP3K7 [cytosol]	Protein	O43318 (Uniprot-TrEMBL)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	ADP	Arrow	REACT_6848 (Reactome)
	ADP	Arrow	REACT_6935 (Reactome)
AGER ligands:AGER		Arrow	REACT_6906 (Reactome)
ATP			REACT_6848 (Reactome)
ATP			REACT_6935 (Reactome)
	Activated IKK Complex	Arrow	REACT_6935 (Reactome)
Activated IKK Complex		mim-catalysis	REACT_6848 (Reactome)
Activated TAK complexes		mim-catalysis	REACT_6935 (Reactome)
IKKA:IKKB:NEMO			REACT_6935 (Reactome)
IkBs:NFkB			REACT_6848 (Reactome)
	NFkB Complex	Arrow	REACT_6848 (Reactome)
	NFkB Complex	Arrow	REACT_6906 (Reactome)
NFkB Complex			REACT_6906 (Reactome)
	Phospho-NF-kappaB Inhibitor	Arrow	REACT_6848 (Reactome)
			REACT_6848 (Reactome)	In human, IkB is an inhibitory protein that sequesters NF-kB in the cytoplasm, by masking a nuclear localization signal, located just at the C-terminal end in each of the NF-kB subunits. A key event in NF-kB activation involves phosphorylation of IkB by an IkB kinase (IKK). The phosphorylation and ubiquitination of IkB kinase complex is mediated by two distinct pathways, either the classical or alternative pathway. In the classical NF-kB signaling pathway, the activated IKK (IkB kinase) complex, predominantly acting through IKK beta in an IKK gamma-dependent manner, catalyzes the phosphorylation of IkBs (at sites equivalent to Ser32 and Ser36 of human IkB-alpha or Ser19 and Ser22 of human IkB-beta); Once phosphorylated, IkB undergoes ubiquitin-mediated degradation, releasing NF-kB.
			REACT_6906 (Reactome)	NFkB is a family of transcription factors that play pivotal roles in immune, inflammatory, and antiapoptotic responses. There are five NF-kB/Rel family members, p65 (RelA), RelB, c-Rel, p50/p105 (NF-kappa-B1) and p52/p100 (NFkappa-B2), All members of the NFkB family contain a highly conserved DNA-binding and dimerization domain called Rel-homology region (RHR). The RHR is responsible for homo- or heterodimerization. Therefor, NF-kappa-B exists in unstimulated cells as homo or heterodimers; the most common heterodimer is p65/p50. NF-kappa-B is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins called IkBs, which mask the nuclear localization signal of NF-kB and prevent its nuclear translocation. Various stimuli induce the activation of the IkB kinase (IKK) complex, which then phosphorylates IkBs. The phosphorylated IkBs are ubiquitinated and then degraded through the proteasome-mediated pathway. The degradation of IkBs releases NF-kappa-B and and it can be transported into nucleus where it induces the expression of target genes.
			REACT_6935 (Reactome)	In humans, the IKKs - IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. The IKK complex contains two catalytic subunits, IKK alpha and IKK beta associated with a regulatory subunit, NEMO (IKKgamma). The activation of the IKK complex and the NFkB mediated antiviral response are dependent on the phosphorylation of IKK alpha/beta at its activation loop and the ubiquitination of NEMO [Solt et al 2009; Li et al 2002]. NEMO ubiquitination by TRAF6 is required for optimal activation of IKKalpha/beta; it is unclear if NEMO subunit undergoes K63-linked or linear ubiquitination. This basic trimolecular complex is referred to as the IKK complex. Each catalytic IKK subunit has an N-terminal kinase domain and leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-terminal NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs. IKK beta is the major IKK catalytic subunit for NF-kB activation. Phosphorylation in the activation loop of IKK beta requires Ser177 and Ser181 and thus activates the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.